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#29029327   2017/10/13 Save this To Up

The exonization and functionalization of an Alu-J element in the protein coding region of glycoprotein hormone alpha gene represent a novel mechanism to the evolution of hemochorial placentation in primates.

Alu elements contribute considerably to gene regulation and genome evolution in primates. The generation of new exons from Alu elements has been found in various human genes, and the regulatory function of the Alu exon has been investigated in many studies. However, the functionalization of Alu elements in protein coding regions remains unknown. Here, we reported that an Alu-J element exonized in the glycoprotein hormone alpha (GPHA) gene and encoded an additional N-terminal peptide (Alu-J encoding peptide) of the mature GPHA peptide, leading to a splicing variant of Alu-GPHA in anthropoid primates approximately 35 million years ago. Interestingly, adaptive evolution of the Alu-J exon occurred in the human and ape lineages during anthropoid evolution. The Alu-J encoding peptide is found to be a new biomarker in human early pregnancy and prolongs the serum half-life of human chorionic gonadotropin (HCG) circulation. Moreover, Alu-J encoding peptide enhances the bioactivity of HCG protein, both in vivo and in vitro. Our study reveals the first example of an Alu element functioning as the encoding peptide to increase the whole protein stability and provides insight into the potential multi-functionalization of the Alu exon in the protein coding regions. Furthermore, with the chorionic gonadotropin (CG) linking with hemochorial placentation, the exonization and functionalization of the Alu-J exon in GPHA gene represent a novel mechanism to the evolution of hemochorial placentation in primates.

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#29029225   2017/10/13 Save this To Up

Glucocorticoid Signaling in Health and Disease: Insights from Tissue-Specific GR Knockout Mice.

Glucocorticoids are adrenally produced hormones critically involved in development, general physiology, and control of inflammation. Since their discovery, glucocorticoids have been widely utilized to treat a variety of inflammatory conditions. However, high doses or prolonged use leads to a number of side-effects throughout the body, which preclude their clinical utility. The primary actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a transcription factor that regulates many complex signaling pathways. Although GR is nearly ubiquitous throughout the body, glucocorticoids exhibit cell- and tissue-specific effects. For example, glucocorticoids stimulate glucose production in the liver, reduce glucose uptake in the skeletal muscle, and decrease insulin secretion from the pancreatic β-cells. Mouse models represent an important approach to understanding the dynamic functions of GR signaling in normal physiology, disease, and resistance. In that absence of a viable GR null model, gene-targeting techniques utilizing promoter driven recombination have provided an opportunity to characterize the tissue-specific actions of GR. The aim of the present review is to describe the organ systems in which GR has been conditionally deleted and summarize the functions ascribed to glucocorticoid action in those tissues.

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#29029202   2017/10/13 Save this To Up

A Metabolomic Signature of Acute Caloric Restriction.

The experimental paradigm of acute caloric restriction followed by refeeding can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss.

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#29029102   2017/10/13 Save this To Up

Nucleos(t)ide Analogue Treatment for Adult Patients with HBeAg-positive Chronic Infection with Genotype C Hepatitis B Virus: A Nationwide Real-life Study.

Antiviral treatment for patients in HBeAg-positive chronic hepatitis B virus (HBV) infection is still controversial. We assessed whether antiviral treatment reduces liver disease progression in those patients.

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#29029094   2017/10/13 Save this To Up

Thyroid hormone metabolism defects in a mouse model of SBP2 deficiency.

SBP2 (selenocysteine insertion sequence binding protein 2) is an essential factor in selenoprotein synthesis. Patients with SBP2 defects have a characteristic thyroid phenotype and additional manifestations such as growth delay, male infertility, impaired motor coordination and developmental delay. The thyroid phenotype has become pathognomonic for this defect and putative deficiencies in the iodothyronine deiodinases selenoenzymes have been implicated. To investigate the role of SBP2 and selenoproteins in thyroid physiology and answer questions raised by the human syndrome we generated a tamoxifen inducible Sbp2 conditional knockout (iCKO) mouse model. These Sbp2 deficient mice have high serum T4, TSH and rT3, similar to the human phenotype of SBP2 deficiency, while serum T3 is normal. Their liver T4 and T3 content reflect the serum levels, and deiodinase 1 expression and enzymatic activity were decreased. In contrast, brain T3 content is decreased, indicative of local hypothyroidism, confirmed by the decreased expression of the thyroid hormone positively regulated gene hairless. Interestingly, the cerebrum T4 content did not parallel the high serum T4 levels, and the expression of TH transporters was decreased. Deiodinase 2 enzymatic activity and deiodinase 3 expression were decreased in cerebrum. The expression and/or activity of other selenoproteins were decreased in brain, liver and serum, thus demonstrating a global deficiency in selenoprotein synthesis. Sbp2 iCKO mice replicate the thyroid phenotype of SBP2 deficiency and represent an important tool to advance our understanding of the role of SBP2 in thyroid homeostasis and for investigating selenoprotein biology relevant to human disease.

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#29029085   2017/10/13 Save this To Up

Impairment of elastic properties of the aorta in bicuspid aortic valve: relationship between biomolecular and aortic strain patterns.

Bicuspid aortic valve (BAV) is associated with aortic wall alterations. We aimed to detect any correlation between aortic elasticity and genetic and biomolecular patterns of elastin.

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#29029077   2017/10/13 Save this To Up

Association of obesity, diabetes, and risk of tuberculosis: two population-based cohorts.

Mounting data has revealed that body mass index (BMI) is inversely associated with risk of active tuberculosis. The inverse association presents a "paradox" with regard to diabetes, since obesity is a major determinant of diabetes, and diabetes is a well-known risk factor for tuberculosis.

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#29029058   2017/10/13 Save this To Up

Inter-ethnic differences in valve morphology, valvular dysfunction, and aortopathy between Asian and European patients with bicuspid aortic valve.

Transcatheter aortic valve replacement (TAVR) has been shown safe and feasible in patients with bicuspid aortic valve (BAV) morphology. Evaluation of inter-ethnic differences in valve morphology and function and aortic root dimensions in patients with BAV is important for the worldwide spread of this therapy in this subgroup of patients. Comparisons between large European and Asian cohorts of patients with BAV have not been performed, and potential differences between populations may have important implications for TAVR.

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#29029054   2017/10/13 Save this To Up

Prostaglandin-endoperoxide synthase 1 (Ptgs1) mediates the timing of parturition in mice despite unhindered uterine contractility.

Cyclooxygenase (COX)-derived prostaglandins stimulate uterine contractions and prepare the cervix for parturition. Prior reports suggest Cox-1 (Ptgs1) knockout (KO) mice exhibit delayed parturition due to impaired luteolysis, yet the mechanism for late-onset delivery remains unclear. Here, we examined key factors for normal onset of parturition to determine whether any could account for the delayed parturition phenotype. Pregnant Cox-1KO mice did not display altered timing of embryo implantation or post-implantation growth. Although mRNAs of contraction-associated proteins (CAPs) were differentially expressed between Cox-1KO and wild-type (WT) myometrium, there were no differences in: CAP agonist-induced intracellular-Ca2+ release, spontaneous or oxytocin (OT)-induced ex vivo uterine contractility, or in vivo uterine contractile pressure. Delayed parturition in Cox-1KO mice persisted despite exogenous OT treatment. Progesterone (P4)-withdrawal, by ovariectomy or administration of the P4-antagonist RU486, diminished the delayed parturition phenotype of Cox-1KO mice. Since antepartum P4 levels fail to decline in Cox-1KO females, P4-treated WT mice were examined for the effect of this hormone on in vivo uterine contractility and ex vivo cervical dilation. P4-treated WT mice had delayed parturition but normal uterine contractility. Cervical distensibility was decreased in Cox-1KO mice on the day of expected delivery and reduced in WT mice with long-term P4-treatment. Collectively, these findings show that delayed parturition in Cox-1KO mice is the result of impaired luteolysis and cervical dilation, despite the presence of strong uterine contractions.

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#29029035   2017/10/13 Save this To Up

Long-term survival and causes of death in patients with ST-elevation acute coronary syndrome without obstructive coronary artery disease.

We aimed to study survival and causes of death in patients with ST-elevation acute coronary syndrome (STE-ACS) with and without obstructive coronary artery disease (CAD).

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